Identification of Gedunin from a Phytochemical Depository as a Novel Multidrug Resistance-Bypassing Tubulin Inhibitor of Cancer Cells
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Sami A Khalid
- Mona Dawood
- Joelle C Boulos
- Monica Wasfi
- Assia Drif
- Faranak Bahramimehr
- Nasim Shahhamzehei
- Letian Shan
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000858765100001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.3390/molecules27185858
- eISSN
- 1420-3049
- Externe Identifier
- Clarivate Analytics Document Solution ID: 4U4KQ
- PubMed Identifier: 36144591
- Ausgabe der Veröffentlichung
- 18
- Zeitschrift
- MOLECULES
- Schlüsselwörter
- cancer
- microtubuli
- natural product
- network pharmacology
- targeted chemotherapy
- Artikelnummer
- ARTN 5858
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Titel
- Identification of Gedunin from a Phytochemical Depository as a Novel Multidrug Resistance-Bypassing Tubulin Inhibitor of Cancer Cells
- Sub types
- Article
- Ausgabe der Zeitschrift
- 27
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Abstract
- <jats:p>The chemotherapy of tumors is frequently limited by the development of resistance and severe side effects. Phytochemicals may offer promising candidates to meet the urgent requirement for new anticancer drugs. We screened 69 phytochemicals, and focused on gedunin to analyze its molecular modes of action. Pearson test-base correlation analyses of the log10IC50 values of 55 tumor cell lines of the National Cancer Institute (NCI), USA, for gedunin with those of 91 standard anticancer agents revealed statistically significant relationships to all 10 tested microtubule inhibitors. Thus, we hypothesized that gedunin may be a novel microtubule inhibitor. Confocal microscopy, cell cycle measurements, and molecular docking in silico substantiated our assumption. Agglomerative cluster analyses and the heat map generation of proteomic data revealed a subset of 40 out of 3171 proteins, the expression of which significantly correlated with sensitivity or resistance for the NCI cell line panel to gedunin. This indicates the complexity of gedunin’s activity against cancer cells, underscoring the value of network pharmacological techniques for the investigation of the molecular modes of drug action. Finally, we correlated the transcriptome-wide mRNA expression of known drug resistance mechanism (ABC transporter, oncogenes, tumor suppressors) log10IC50 values for gedunin. We did not find significant correlations, indicating that gedunin’s anticancer activity might not be hampered by classical drug resistance mechanisms. In conclusion, gedunin is a novel microtubule-inhibiting drug candidate which is not involved in multidrug resistance mechanisms such as other clinically established mitotic spindle poisons.</jats:p>
- Autoren
- Sami A Khalid
- Mona Dawood
- Joelle C Boulos
- Monica Wasfi
- Assia Drif
- Faranak Bahramimehr
- Nasim Shahhamzehei
- Letian Shan
- Thomas Efferth
- DOI
- 10.3390/molecules27185858
- eISSN
- 1420-3049
- Ausgabe der Veröffentlichung
- 18
- Zeitschrift
- Molecules
- Sprache
- en
- Online publication date
- 2022
- Paginierung
- 5858 - 5858
- Status
- Published online
- Herausgeber
- MDPI AG
- Herausgeber URL
- http://dx.doi.org/10.3390/molecules27185858
- Datum der Datenerfassung
- 2022
- Titel
- Identification of Gedunin from a Phytochemical Depository as a Novel Multidrug Resistance-Bypassing Tubulin Inhibitor of Cancer Cells
- Ausgabe der Zeitschrift
- 27
Data source: Crossref
- Abstract
- The chemotherapy of tumors is frequently limited by the development of resistance and severe side effects. Phytochemicals may offer promising candidates to meet the urgent requirement for new anticancer drugs. We screened 69 phytochemicals, and focused on gedunin to analyze its molecular modes of action. Pearson test-base correlation analyses of the log<sub>10</sub>IC<sub>50</sub> values of 55 tumor cell lines of the National Cancer Institute (NCI), USA, for gedunin with those of 91 standard anticancer agents revealed statistically significant relationships to all 10 tested microtubule inhibitors. Thus, we hypothesized that gedunin may be a novel microtubule inhibitor. Confocal microscopy, cell cycle measurements, and molecular docking in silico substantiated our assumption. Agglomerative cluster analyses and the heat map generation of proteomic data revealed a subset of 40 out of 3171 proteins, the expression of which significantly correlated with sensitivity or resistance for the NCI cell line panel to gedunin. This indicates the complexity of gedunin's activity against cancer cells, underscoring the value of network pharmacological techniques for the investigation of the molecular modes of drug action. Finally, we correlated the transcriptome-wide mRNA expression of known drug resistance mechanism (ABC transporter, oncogenes, tumor suppressors) log<sub>10</sub>IC<sub>50</sub> values for gedunin. We did not find significant correlations, indicating that gedunin's anticancer activity might not be hampered by classical drug resistance mechanisms. In conclusion, gedunin is a novel microtubule-inhibiting drug candidate which is not involved in multidrug resistance mechanisms such as other clinically established mitotic spindle poisons.
- Addresses
- Faculty of Pharmacy, University of Science & Technology, Omdurman, Sudan.
- Autoren
- Sami A Khalid
- Mona Dawood
- Joelle C Boulos
- Monica Wasfi
- Assia Drif
- Faranak Bahramimehr
- Nasim Shahhamzehei
- Letian Shan
- Thomas Efferth
- DOI
- 10.3390/molecules27185858
- eISSN
- 1420-3049
- Externe Identifier
- PubMed Identifier: 36144591
- PubMed Central ID: PMC9501561
- Open access
- true
- ISSN
- 1420-3049
- Ausgabe der Veröffentlichung
- 18
- Zeitschrift
- Molecules (Basel, Switzerland)
- Schlüsselwörter
- Cell Line, Tumor
- Neoplasms
- Limonins
- Tubulin
- ATP-Binding Cassette Transporters
- RNA, Messenger
- Antineoplastic Agents
- Poisons
- Proteomics
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm
- Tubulin Modulators
- Molecular Docking Simulation
- Phytochemicals
- Sprache
- eng
- Medium
- Electronic
- Online publication date
- 2022
- Open access status
- Open Access
- Paginierung
- 5858
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2022
- Titel
- Identification of Gedunin from a Phytochemical Depository as a Novel Multidrug Resistance-Bypassing Tubulin Inhibitor of Cancer Cells.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 27
Files
https://www.mdpi.com/1420-3049/27/18/5858/pdf?version=1663652994 https://europepmc.org/articles/PMC9501561?pdf=render
Data source: Europe PubMed Central
- Abstract
- The chemotherapy of tumors is frequently limited by the development of resistance and severe side effects. Phytochemicals may offer promising candidates to meet the urgent requirement for new anticancer drugs. We screened 69 phytochemicals, and focused on gedunin to analyze its molecular modes of action. Pearson test-base correlation analyses of the log10IC50 values of 55 tumor cell lines of the National Cancer Institute (NCI), USA, for gedunin with those of 91 standard anticancer agents revealed statistically significant relationships to all 10 tested microtubule inhibitors. Thus, we hypothesized that gedunin may be a novel microtubule inhibitor. Confocal microscopy, cell cycle measurements, and molecular docking in silico substantiated our assumption. Agglomerative cluster analyses and the heat map generation of proteomic data revealed a subset of 40 out of 3171 proteins, the expression of which significantly correlated with sensitivity or resistance for the NCI cell line panel to gedunin. This indicates the complexity of gedunin's activity against cancer cells, underscoring the value of network pharmacological techniques for the investigation of the molecular modes of drug action. Finally, we correlated the transcriptome-wide mRNA expression of known drug resistance mechanism (ABC transporter, oncogenes, tumor suppressors) log10IC50 values for gedunin. We did not find significant correlations, indicating that gedunin's anticancer activity might not be hampered by classical drug resistance mechanisms. In conclusion, gedunin is a novel microtubule-inhibiting drug candidate which is not involved in multidrug resistance mechanisms such as other clinically established mitotic spindle poisons.
- Date of acceptance
- 2022
- Autoren
- Sami A Khalid
- Mona Dawood
- Joelle C Boulos
- Monica Wasfi
- Assia Drif
- Faranak Bahramimehr
- Nasim Shahhamzehei
- Letian Shan
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/36144591
- DOI
- 10.3390/molecules27185858
- eISSN
- 1420-3049
- Externe Identifier
- PubMed Central ID: PMC9501561
- Ausgabe der Veröffentlichung
- 18
- Zeitschrift
- Molecules
- Schlüsselwörter
- cancer
- microtubuli
- natural product
- network pharmacology
- targeted chemotherapy
- ATP-Binding Cassette Transporters
- Antineoplastic Agents
- Cell Line, Tumor
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm
- Limonins
- Molecular Docking Simulation
- Neoplasms
- Phytochemicals
- Poisons
- Proteomics
- RNA, Messenger
- Tubulin
- Tubulin Modulators
- Sprache
- eng
- Country
- Switzerland
- PII
- molecules27185858
- Datum der Veröffentlichung
- 2022
- Status
- Published online
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2022
- Titel
- Identification of Gedunin from a Phytochemical Depository as a Novel Multidrug Resistance-Bypassing Tubulin Inhibitor of Cancer Cells.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 27
Data source: PubMed
- Beziehungen:
-